In 1987, the National Institue of Arhritis and Musculoskeletal and Skin Diseases (NIAMS) established "Specialized Centers of Research" (SCORs) in osteoarthritis, a degenerative joint disease. A SCOR, envisioned to be a national resource associated with a major medical center, is dedicated to translating basic research into clinical applications. The overall objectives of SCOR programs are to expedite the development and application of new knowledge, to learn more about the etiology of diseases, and to foster improved approaches to treatment and/or prevention. A SCOR consists of at least three individual, but interrelated, research projects devoted to a specific major health area, each with high scientific merit and clear research objectives. Each SCOR provides a multidisciplinary approach that utilizes both laboratory and patient-oriented clinical research, to focus on a particular health problem and foster a mutually supportive interaction between basic scientists and clinical investigators.

In 1987, under the leadership of the Rush Medical College Department of Biochemistry chairman, Klaus E. Kuettner, PhD, a multidisciplinary team of Rush investigators from the departments of Biochemistry, Orthopedic Surgery, Rheumatology and Anatomy, was awarded one of the three initial SCOR grants in osteoarthritis. Progress on the Rush SCOR, "Osteoarthritis: A Continuum - From Cartilage Metabolism to Early Detection and Treatment" was evalutated by a NIAMS review board in 1992 and 1997. At each review, the Rush SCOR was the sole SCOR grant in osteoarthritis renewed or awarded. In 2003, an additional period of five years was awarded to the Rush SCOR. For 16 years, until mid-2003, this SCOR grant in OA remained under the leadership of Klaus E. Kuettner, PhD, Professor of Biochemistry and Orthopedic Surgery. Starting September 2003, the principal investigator of Rush SCOR in OA will be Theodore Oegema, PhD, who became the chairman of the Department of Biochemistry in 2002.

The specific objectives of the Rush SCOR in OA are to establish and strengthen a "continuum of research," beginning with a better understanding of the basic biochemistry of normal cartilage and ending with a clinical focus on the analysis of the functional biomechanics of treatment of symptomatic OA. The research focuses on the biochemistry of cartilage, the structure and function of the extarcellular matrix components of cartilage and the role of living chondrocytes in producing and maintaining this matrix. Studies on the extracellular matrix have shown that articular cartilage is a dynamic tissue that can withstand considerable fluctating loads by virtue of its hydroelastic properties.
Questions asked include:

How do articular chondrocytes, existing as individual satellite metabolic centers, control the integrity of the extracellular matrix?

How do these cells "sense" that some of the matrix has been removed and needs to be replaced?

How do different anatomical, joint specific and biomechanical environments affect the articular chondrocytes?

The simplest explanation for the etiology of asteoarthritis, which may be regarded as a disease of the cartilage matrix, may be aberrations in the metabolism of chondrocytes. The degeneration of cartilage results from a process of self-destruction, or "chondrcytic chondrolysis," in which excessive catabolism of the cartilage matrix by chondrocytes is not appropriately balanced by synthesis of new matrix. Although biomechanical factors are implicated, which stimuli induce and regulate the hyperactive phenotype of asteoarthritic chondrocytes remains unclear, including their inability to properly repair the extracellular matrix. Future developments in research on osteoarthritis are dependent on a better understanding of the metabolism of normal cartilage and the subsequent modulation of this metabolism by biochemical and biomechanical factors as they may occur in the disease state.

The theme of the ongoing Rush SCOR in OA focuses on the specificity of the following integrated and overlapping processes as they relate to the etiology, diagnosis and treatment of asteoarthritis:

The effect on the metabolism of articular chondrocytes and proteoglycan and/or collagen synthesis as chondrocyte metabolism is modulated by biological and biomechanical stimuli.

The control of endogenous and exogenous cartilage degradation by built-in defense mechanism.

The potential of chondrocytes to repair the tissue following injury.

The process of "chondrocytic chondrolysis" will continue to be investigated.

Focusing on the cell biology and biochemistry of articular cartilage, major research segments will include the molecular analysis of genes crticial to cartilage biology. One novel approach to this aim is to analyze the potential of cells derived from damaged and degenerated cartilage to develop neo-cartilage in vitro [Project 1]. this approach addresses the question of whether genetic/epigenetic changes or damage to the extracellular matrix alone are responsible for disease progression. If particular target genes are found to be altered, molecular ``rescue'' approaches will be used to validate their role. Previous work has also identified a protein that is selectively expressed by articular chondrocytes within the superficial layer (superficial zone proten, SZP). The goal of Project 2 is to characterize the promoter region of SZP and to identify cis-element binding sites within the promoter that regulate SZP transcription at the molecular level as well as the environmental factors (e.g., cytokines) that modulate SZP expression at the cellular level. A special focus remains on comparative studies of tissues from human knee and ankle joints. Previous Rush SCOR-sponsored studies have revealed distinct differences in composition and metabolism that may predispose the knee joint to and/or protect the ankle joint from progressive degeneration. Differences between chondrocytes of the superficial layer of articular cartilages versus deeper layers have also been documented. The current project takes the examination of these chondrocyte populations to the next level, namely, documenting differences in gene expression, sensitivity to specific cytokines, and response to static/dynamic loading [Project 3]. The clinical research project [Project 4] evaluates the effects of a nonsurgical intervention approach designed ot reduce medial knee OA pain as well as the adduction moment. A lateral-wedged contoured orthotic device will be used in human subjects and clinical as well as biochemical (i.e.,serum markers) outcome measures are being collected.

This broad framework allows the Rush SCOR program to include two distinct but overlapping approaches to osteoarthritis. The systematic and metabolic approach is primarily concernred with changes in chondrocyte and cartilage metabolism, adopting the molecular paradigms of the biochemist and the cell biologist. The second, more macroscopic approach, is concerned with the local biomechanical factors that determine the responsiveness of the joint as an organ and the consequences of a non-surgical intervention. Osteoarthritis is, after all, a fairly localized disease and probably not systemically manifested. This approach uses the paradigms of the biomechanician in the gait laboratory and the practicing rheumatologist and combines their efforst to look at the disease as organ physiologists. The studies of this SCOR at Rush encompass four individual yet overlapping projects supported by two Core Facilities.

Project 1: "Mechanism Involved in the Formation of a Cartilage Tissue by Osteoarthritic Cells"